The field of invention is the design and synthesis of compounds, useful in photodynamic therapy and related applications of photoactive compound technology. In particular, the present invention relates to methods to modify polypyrrolic macrocycle compounds, such as porphyrins, via a 1,3-dipolar cycloaddition reaction to produce intermediates that may be further derivatized to produce unique polypyrrolic macrocycle derivatives. In particular, the invention relates to the use of the carbonyl ylide class of 1,3-dipoles to modify polypyrrolic macrocycle compounds and produce intermediates for further derivatization by conventional chemical reactions. The invention also relates to the resulting compounds as members of this class. The resultant polypyrrolic macrocycle derivatives produced via such intermediates are useful as:
photosensitizers for photodynamic therapy;
chelators for radionuclides;
MRI contrast agents (i.e., chelators for paramagnetic metals);
other biomedical uses; and
technical uses for infrared absorbing dyes, such as imaging, data recording and printing.
Photodynamic therapy (PDT) generally involves the administration of compounds that are capable of absorbing light, typically in the visible range, but also in the near ultraviolet, followed by irradiation of locations in the subject for which a toxic, modifying or inhibitory effect is desired. PDT was initially developed using hematoporphyrin and related compounds in the treatment of tumors, as it appeared that these compounds would xe2x80x9chomexe2x80x9d to locations containing rapidly dividing cells. The tumor could then be irradiated with light absorbed by the hematoporphyrin and destruction of the surrounding tissue resulted. PDT has since been shown to be useful for treatment of atherosclerotic plaques, restenosis, infections in the blood stream, rheumatoid arthritis, psoriasis and in the treatment of ocular conditions not necessarily limited to tumors.
U.S. Pat. No. 5,171,749 and patents issuing on related applications, U.S. Pat. Nos. 5,283,255; 5,399,583; 4,883,790; 4,920,143; 5,095,030; and 5,990,149; all of which are incorporated herein by reference, describe and claim a class of photoactive compounds useful in PDT designated the monohydrobenzoporphyrins, or xe2x80x9cBPDs.xe2x80x9d This class is obtained by Diels-Alder reaction of a mono- or disubstituted alkyne with protoporphyrin-IX and the resultant compounds can further be isomerized, reduced, and/or derivatized to obtain a large class of BPDs. As disclosed in these patents, a particularly useful subclass of this group results from hydrolysis or partial hydrolysis of the ester groups of the 2-carboxylethyl side-chains on rings C and D. Esterification as protection of these groups during the Diels-Alder reaction results in initial products which contain 2-carbalkoxyethyl groups. It was found that facile hydrolysis of these esters could readily be conducted, leaving any carbalkoxy groups associated with the Diels-Alder product obtained from a dicarbalkoxyalkyne virtually completely unhydrolyzed.
Another means of derivatizing porphyrin compounds by use of osmium tetroxide has been previously described in U.S. Pat. No. 5,648,485 issued Nov. 3, 1998, which is hereby incorporated by reference as if fully set forth.
There remains, however, a continuing need to improve PDT by the production of additional derivatives of known polypyrrolic macrocycle photosensitizers or by the use of improved methods of synthesizing known polypyrrolic macrocycle photosensitizers.
The methods and compounds of the invention provide particularly useful new additions to the repertoire of compounds useful in photodynamic therapy (PDT) as well as means to expand this repertoire in a methodical fashion. The methods of the invention take advantage of the ability to modify polypyrrolic macrocycles by the use of a 1,3-dipolar cycloaddition reaction (see Huisgen, R., Angew. Chem. 1963, 75, 604; Huisgen, R., Angew. Chem. 1968, 80, 329; and Huisgen, R., Proc. Chem. Soc. 1961, 357). These types of reactions have become prominent in organic chemistry due to the vast number of bonds that undergo transformations (see Bianchi, G.; et al. In The Chemistry of Functional Groups A; Patai, S. Ed., Interscience: New York, 1977, 369; Stuckwisch, C. G., Synthesis 1973, 469; and Kaufmann, T., Angew Chem. Int. Ed. Engl. 1974, 13, 627). A xe2x80x9c1,3-dipolexe2x80x9d is a species that is represented by a zwitterionic octet structure and undergoes 1,3-cycloadditions with a multiple-bond system, the xe2x80x9cdipolarophile.xe2x80x9d The 1,3-dipolar cycloaddition is a [3+2xe2x86x925] cycloaddition which normally forms a five-membered heterocyclic ring. The ring closure is effected by cyclic electron shifts which form two new "sgr" bonds at the expense of xcfx80 bonds. Over 18 different types of 1,3-dipoles have been employed in such reactions, presenting numerous possibilities for variation over and above the variety due to the wide diversity of the nature of the dienophile.
All 1,3-dipoles incorporate an onium center whose positive charge neutralizes the negative charge on one of the terminal atoms to form a heteroallyl anion which bears no net charge. Two of the four allylic xcfx80 electrons can be delocalized at the center atom. The terminal centers of the dipoles can be either nucleophilic or electrophilicxe2x80x94the key to the reactivity of all 1,3-dipoles.
Formally, there are two types of 1,3-dipoles: those in which the central atom is sp-hybridized and those whose central atom is sp2-hybridized. The later group have allyl anion type xcfx80 systems with four electrons in three parallel atomic xcfx80 orbitals perpendicular to the plane of the dipole. This type of 1,3-dipole is bent and the central atom can be oxygen, nitrogen or sulfur 1,3-Dipoles having an sp-hybridized central atom are referred to as propargyl or allenyl types. These are linear and the central atom is confined to nitrogen.
1,3-dipolar cycloadditions with tetraphenylporphyrins have been previously attempted with diazoacetate and diazomethane (see Smith, K. M., et al. Tetrahedron Lett. 1990, 31, 3853). Cavaleiro et al. have performed a number of Diels-Alder reactions with tetraphenylporphyrins (Faustino, M. A. F., et al. Tetrahedron Lett. 1996, 37, 3569; and Tomxc3xa9, A. C., et al. J. Chem. Soc., Chem. Comm. 1997, 1199). Cavaleiro et al. also reported the dienophile-like nature of meso-tetraphenylporphyrins (see Tomxc3xa9 above).
While at least eight different classes of 1,3-dipoles (carbonyl ylides, nitrile oxides, diazoalkanes, azides, azomethine ylides, nitrile ylides, nitrones and azomethine imines) are potentially reactive and/or reactive towards aromatic systems, the present invention is directed to the use of carbonyl ylides in the modification of polypyrrolic macrocycle photosensitizers. While any carbonyl ylide may be used in the practice of the invention, preferred ylides are those that result in the modification of a polypyrrolic macrocycle to contain one or more cyano groups.
In a preferred aspect, the invention is directed to the modification of a polypyrrolic macrocycle with a carbonyl ylide to produce an intermediate compound containing one or more cyano groups. Such groups can then be used as functionalities for further derivatization of the compounds to produce macrocycles of interest.
Preferred derivative macrocycles are represented by the formulas 
wherein formula I represents the structure of a polypyrrolic macrocycle of the invention and formula II represents the structure of the metallated form of the macrocycle. M is a metal selected from the group consisting of Ni(II), Cu(II), Zn(II), Fe(III)Cl, Sn, Ge, Si, Ga, Al, Mn(III), Gd(III), In and Tc;
R1 through R6 are independently a hydrogen atom, a lower alkyl group, a lower alkyl carboxylic acid or acid ester group, keto, hydroxy, nitro, amino or a group that, taken together with another ring, ring substituent or meso-substituent, forms a fused 5- or 6-membered ring.
Similarly, Rx and Ry are substituents formed from further derivatization of moieties introduced upon 1,3-dipolar cycloaddition to the macrocycle. Preferably, the cycloaddition results in a macrocycle intermediate containing one or more cyano groups. Upon further derivatization, Rx and Ry are independently selected from the group consisting of a hydrogen atom, a lower alkyl group, a lower alkyl carboxylic acid or acid ester group, keto, hydroxy, nitro, amino or a group that, taken together with another ring, ring substituent or meso-substituent, forms a fused 5- or 6-membered ring.
With respect to all Rn groups, the other group covalently bonded to the carbon atom to which the Rn is attached may be independently a hydrogen atom or a hydroxyl group.
Ph1, Ph2, Ph3 and Ph4 independently represent a group selected from H, substituted or unsubstituted alkyl groups, or substituted or unsubstituted aromatic rings, which may be the same or different.
Also included within the scope of the formulas are the salts and the metallated and/or labeled and/or conjugated forms thereof.
The invention is also directed to methods to make the compounds of the formula by modification of a base polypyrrolic macrocycle with a carbonyl ylide to form an intermediate which may then be subsequently isomerized, reduced, and/or derivatized.
Also included in the invention as a preferred embodiment are the intermediates and derivative compounds involved in the production of the formula and pharmaceutical compositions containing these compounds as well a methods to perform PDT using them.